Proton nanomodulators for enhanced Mn2+-mediated chemodynamic therapy of tumors via HCO3− regulation

Background Mn 2+ -mediated chemodynamic therapy (CDT) has been emerged as a promising cancer therapeutic modality that relies heavily on HCO 3 − level in the system. Although the physiological buffers (H 2 CO 3 /HCO 3 − ) provide certain amounts of HCO 3 − , the acidity of the tumor microenvironment (TME) would seriously affect the HCO 3 − ionic equilibrium (H 2 CO 3 ⇌ H + + HCO 3 − ). As a result, HCO 3 − level in the tumor region is actually insufficient to support effective Mn 2+ -mediated CDT. Results In this study, a robust nanomodulator MnFe 2 O 4 @ZIF-8 (PrSMZ) with the capability of in situ self-regulation HCO 3 − is presented to enhance therapeutic efficacy of Mn 2+ -mediated CDT. Under an acidic tumor microenvironment, PrSMZ could act as a proton sponge to shift the HCO 3 − ionic equilibrium to the positive direction, significantly boosting the generation of the HCO 3 − . Most importantly, such HCO 3 − supply capacity of PrSMZ could be finely modulated by its ZIF-8 shell thickness, resulting in a 1000-fold increase in reactive oxygen species (ROS) generation. Enhanced ROS-dependent CDT efficacy is further amplified by a glutathione (GSH)-depletion ability and the photothermal effect inherited from the inner core MnFe 2 O 4 of PrSMZ to exert the remarkable antitumor effect on mouse models. Conclusions This work addresses the challenge of insufficient HCO 3 − in the TME for Mn 2+ -mediated Fenton catalysts and could provide a promising strategy for designing high-performance Mn 2+ -mediated CDT agents to treat cancer effectively.